The Pima Indians of Arizona have the highest reported prevalence and incidence of non-insulin dependent diabetes mellitus (NIDDM)of any population in the world. Beginning in 1982, a subset of this population has been studied to determine the etiologic factors that predispose non-diabetic individuals to develop the disease. Subjects are admitted yearly to the clinical research ward to undergo body composition analysis, an oral glucose tolerance test, an intravenous glucose tolerance test, a standard mixed meal test, and a two-step hyperinsulinemic, euglycemic clamp to measure insulin action in vivo. Over 400 individuals have entered into the study and approximately 48 subjects have developed NIDDM. Obesity, central obesity, fasting hyperinsulinemia, and insulin resistance are each major risk factors for the development of NIDDM. A low acute insulin response (AIR) to an intravenous glucose bolus is an additional predictor. Longitudinally, in 17 subjects studied at each stage of the development of diabetes, progression to diabetes was associated with weight gain, a 14% decrease in insulin action and a 78% decrease in the AIR. Since each of these factors are familial and predictive of diabetes, it is likely that the genetic determinants of these phenotypes contribute to the pathogenesis of NIDDM, which is known to be largely genetically determined. A genomic scan was recently completed which suggested several loci that may harbor genes for diabetes in this population. The expression and function of candidate genes suggested by this scan and on functional criteria are being examined in skeletal muscle and adipose tissue obtained from selected individuals participating in this protocol.